Succinic acid esters



2,894,983 Patented July 14, 1959 prises the succinic acid semi-esters of the aforementioned 2,894,983 carbinols and their salts with therapeutically utilisable bases, preferably the alkali metals. The carbinols, the SU C C I ESTERS succinic acid semi-esters and the salts thereof have a Herbert Arnold, Bielefeld, and Norbert Brock, Wadersloh, 5 'f actlon' However the carhmols have Olly Germany, assignors to Aswwerke Akfi g u h ft consistency and consequently are unsuitable for the man- Chemische Fabrik, Brackwede, Westphalia, Germany ufacture of the conventional forms of medicines, such as tablets or lozenges. Another disadvantage of the car- No pp February 18, 1958 binols is that they are insoluble'in aqueous medium. The Senal 715,862 succinic acid semi-esters and the salts thereof are of solid Claims priority, application Germany February 23, 1957 Consistency. The salts, especially the alkali metal salts have a good solubility in water. In addition, the semi- 3 Claimsesters and their salts are practically odourless. As regards their cholagogue action, the carbinols and This invention relates to new choleretically active comtheir succinic acid semi-esters are superior to the known pounds and the production thereof. phenyl alkyl carbinols of the following general Formula The new compounds have the following general For- 1V; mllla I: RCH0Y l H IV CH; \CH

CH; 0H 1 (see, for R=rnethyl, W. Kalow, Arch. exper. Path. and in which R represents an alkyl radical with an aliphatic Pharmakol- Pages 696-702 chain containing 1-4 carbon atoms, R represents y y g out comparative Pharmacologwal tests, one of th t o groups .CH=CH a d CH CH its was established that the choleretic action with a com- Y represents a member of the group consisting of the pound of the general Formula II wherein R TGPI'CSGDIS a hydrogen atom and the radicals methyl radical is increase: two-fold uzis compaged witRh the comparable compoun of Form a IV w erein CO' CHZ CHZ COOX represents a methyl radical, whereas, with a compound and X represents a member of the group consisting of of the general Formula III wherein R represents a methyl the hydrogen atom and the salt-forming radicals, preferradical, a therapeutically desirable longer effective period ably the alkali metals. is obtained as compared with the corresponding product The aliphatic chain of the alkyl radicals R may be of Formula IV, with like effective intensity. The eflective straight or branched. period of compound III (R=m'eth'yl) is about three If Y in the above general Formula I represents a hyhours and f GQ P I V (R m t yl) ut tw drogen atom, the general Formula I comprises the se hours. Since the toxicities of the known'substance IV in ondary alcohols of the general Formulae II and III. 40 which R representS hy radical and of new l stances are substantially the same, the result is that the g therapeutic range is increased for the new compounds of the general Formulae II and III. The same applies as cg CH C 1 CH regards the succinic acid semi-esters and their salts. O I l C a The following table shows the DL values and the DE values and also the therapeutic index for a com- OH H H CH;

g pound in accordance with the invention, namely, the O c 1 sodium salt of the succinic acid semi-ester described in Example 6, as compared with the prior known phenyl in which R has the meaning indicated above. ethanol and the prior known sodium salt of ,B-[l-meth- If Y in the general Formula 1 represents the radical oxy-4-naphthoyll-propionic acid (indicated in the table -'-COCH CH COOX, the general formula I comas Product II).

TABLE DI. DL DELI irii 'a iciii'f 313241 3321 index index Product I.P., Intra- I.P., mmoL/kg. duodenal, mmoL/kg LP. enteral mmoL/kg.

Example 6 4. 2 #31. 6 0.16 26 176 1 5.1 28.7 0.38 12 76 zLS 0. 32 e .crystalline products.

The second vertical column of the table shows the DL values with an intraperitoneal dose. The amount of 4.2 mmoL/kg. corresponds approximately to 1 g./kg.

The third vertical column shows the DL values with an intraduodenal dose. The quantity of 31.6 mmoL/kg. corresponds to a quantity of about 7.5 g./kg.

The fourth vertical column shows the DE values. What is meant here is the dosis efiicax, i.e. the effective dose which increases the gall secretion in two hours to 1.5 times its former value (150% of its former value).

The fifth and sixth vertical columns show the therapeutic indices, i.e. the ratio between the lethal dose (DL and the effective dose (DE The. higher the index, the lower the toxicity of the substance.-

The compounds of the general Formula I can be obtained in accordance with the invention by the following methods:

A. By reacting Grignard compounds (V) with endomethylene-2.S-tetrahydro-M-benzaldehyde (VI) (Ann. der Chemie, 460, 105 [1928] c R.MgHalog. I

v. VI.

B. From the endomethyIene-Z.S-tetrahydro-M-phenylhalides (VII) readily available by diene synthesis (Ann. der Chem. 543, 24 [1940]), by converting these halides into the Grignard compounds (VIII) and reacting these compounds with aldehydes of the general formula R-CHO:

llialogen CH\ cg on on, on on LIIgHaIQg.

03% I o f o of of cn VII. VIII. II.

C. From the 2-acyl-bicyclo-(2,2,l)-hept-5-enes (IX) readily obtainable by diene synthesis (Chem. Zbl. 1948/1, page 320) from cyclopentadiene and vinyl alkyl ketones by reduction of these heptenes by the method of Meerwein and Ponndorf with aluminum isopropylate in isopropyl alcohol:

o I o \CH +12 CHO cg! R-CH-OH (5H cg on c I 0119200 IX. II.

way have in many cases initially an oily consistency;

carefulworking up and purification, -however, produces The salts can for example be ch 4 tained by dissolving the acid semi-esters in aqueous solu-- tions of the salt-forming bases.

The following examples further illustrate the invention:

Example 1 A solution of 160 g. of 2.5-endomethylenesA -cyclohexene aldehyde-( 1) is added dropwise to a Grignard solution prepared from 35 g. of magnesium powder and 187 g. of methyl iodide in ether. When the reaction has ended, heating is continued for 10 minutes on a water bath. The resulting reaction solution then has added thereto an ice-cold aqueous solution of 170 g. of ammonium chloride, and the resulting a-(2.5-endomethylene-A -cyclohexene)-ethanol (of the general Formula II in which R=CH is isolated by extraction with ether and purified by distillation (B.P. 11 mm.=8284 0.). Yield: 150 g.=84% of the theoretical.

Example 2 As described in Example ,1, g. of u-(2.5-endomethylene-A -tetrahydrophenyl)-isobutanol (of the general Formula II in which R=(CH CH) are obtained by a Grignard reaction from 23 g. of magnesium and g. of isopropyl bromide and 104 g. of 2.5-endomethylene A tetrahydrobenzaldehyde in ethereal solution.

Yield: 100 g.=7l% of the theoretical; B.P. 12 mm.=9096 C.; M.P.=90 C.

Example 4 149 g. of a (2.5 endomethylenehexahydrophenyl)+ ethanol (of the general Formula III in which R=CH are obtained from 150 g. of a-(2.5-endomethylene-A tetrahydrophenyl)-ethanol (Example 1) in the presence of Raney nickel at 50 C. and a hydrogen pressure of 100 atm. in methanolic solution. B.P. 12 mm. =87-88 C. Yield: 98% of the theoretical.

Example 5 Under the conditions indicated in Example 4, 148 g. of a-(2.5-endomethylenehexahydrophenyl)-propanol (of the General Formula III in which R=C H are obtained from 150 g. of the corresponding initial material (Example 2). B.P.=9596 C. Yield: 98.6% of the theoretical.

Example 6 330 g. (2.4 mols) of u-(2.5-endomethylene-A -tetrahydrophenyD-ethanol are mixed with 200 g. (2 mols) of succinic acid anhydride and 600 ml. of absolute toluene and the mixture is heated for 16 hours to the: boiling point while stirring. 600 ml. of ether are added to the cooled reaction solution and the toluene-ether.mix-- ture is submitted to extraction with dilute sodium hydroxide solution, with ice cooling, to isolate the succinic acid semi-ester. The aqueous alkali solution is then acidi-- fied again with HCl while cooling with ice and the succiuic acid semi-ester liberated is extracted with ether. The ethereal solution of the ester is dried over Na SO After evaporation of the ether, the residue is subjected to vacuum fractionation. B.P. 0.9 mm.=172 C.; distillation yield: 323 g.=68% of the theoretical.

This distillate is a viscous oil containing a few crystals.

' It is dissolved in 1000 ml. of petroleum ether and kept -for'24 hours in a refrigerator.

After this time, the succinic acid semi-ester has precipitated as a white Example 7 A solution of 44 g. acetaldehyde in 100 ml. ether is added dropwise to a Grignard solution prepared from 26.7 g. of magnesium powder and 128.5 g. of 2.5-endomethylene-A -cyclohexene-chloride in 450 ml. ether. In order to accelerate the reaction the mixture is stirred. When the reaction has ended ice-water and ammonium chloride are added to the reaction mixture which is worked up as described before. An oil is obtained; B.P. 12 mm.=89-91 C.; yield: 70 -g.=50.7% of the theoretical.

Example 8 40.8 g. 2.5-endomethylcue-A -cyclohexenyl-methylketone are reduced with 180 m1. of molar solution of aluminium-isopropylate in isopropanol. The isopropanol is then distilled off. The residue is hydrolysed with dilute soda lye. The carbinol thus obtained is worked up in vacuo and fractionated. BR 11 mm.=87-88 0.; yield 30 g.=73% of the theoretical.

6 What we claim is: 1. The compounds of the formula H Cg CH wherein References Cited in the file of this patent UNITED STATES PATENTS Morris et a1 Feb. 3, 1948 OTHER REFERENCES Alder et al.: Chemical Abstracts 32, 9056 (1938). Chemical Abstracts 43, 10786 (1949). 

1. THE COMPOUNDS OF THE FORMULA 